Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia-reperfusion in mice.

Abstract

Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that plays an important role in renal tubular injury and regeneration in acute kidney injury. However, its role in the development of renal fibrosis, often a long-term consequence of acute kidney injury, is unknown. Using a mouse model of renal fibrosis induced by ischemia-reperfusion injury, we demonstrate increased GSK3β expression and activity in fibrotic kidneys, and its presence in myofibroblasts in addition to tubular epithelial cells. Pharmacological inhibition of GSK3 using TDZD-8 starting before or after ischemia-reperfusion significantly suppressed renal fibrosis by reducing the myofibroblast population, collagen-1 and fibronectin deposition, inflammatory cytokines, and macrophage infiltration. GSK3 inhibition in vivo reduced TGF-β1, SMAD3 activation and plasminogen activator inhibitor-1 levels. Consistently in vitro, TGF-β1 treatment increased GSK3β expression and GSK3 inhibition abolished TGF-β1-induced SMAD3 activation and α-smooth muscle actin (α-SMA) expression in cultured renal fibroblasts. Importantly, overexpression of constitutively active GSK3β stimulated α-SMA expression even in the absence of TGF-β1 treatment. These results suggest that TGF-β regulates GSK3β, which in turn is important for TGF-β-SMAD3 signaling and fibroblast-to-myofibroblast differentiation. Overall, these studies demonstrate that GSK3 could promote renal fibrosis by activation of TGF-β signaling and the use of GSK3 inhibitors might represent a novel therapeutic approach for progressive renal fibrosis that develops as a consequence of acute kidney injury.

• Authors: Shailendra P Singh, Shixin Tao, Timothy A Fields, Sydney Webb, Raymond C Harris, Reena Rao
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 8 Issue 8 Pg. 931-40 (Aug 01 2015) ISSN: 1754-8411 [Electronic] England
• PMID: 26092126 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015. Published by The Company of Biologists Ltd.

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Inflammation Mediators
• Protein Kinase Inhibitors
• Thiadiazoles
• Transforming Growth Factor beta
• beta Catenin
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cell Differentiation (drug effects)
• Cell Line
• Epithelial Cells (drug effects, metabolism)
• Extracellular Matrix (drug effects, metabolism)
• Fibroblasts (drug effects, enzymology, pathology)
• Fibrosis
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 beta
• Inflammation Mediators (metabolism)
• Kidney (drug effects, enzymology, pathology)
• Macrophages (drug effects, metabolism)
• Mice, Inbred C57BL
• Myofibroblasts (drug effects, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Reperfusion Injury (drug therapy, enzymology, pathology)
• Signal Transduction (drug effects)
• Thiadiazoles (pharmacology, therapeutic use)
• Transforming Growth Factor beta (metabolism)
• beta Catenin (metabolism)